Tachykinins are a family of peptides which share the common amidated carboxy terminal sequence,
Phe-Xaa-Gly-Leu-Met-NH.sub.2 PA1 Arg-Pro-Lys-Pro-Gln-Gin-Phe-Phe-Gly-Leu-Met-NH.sub.2 PA1 His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH.sub.2 PA1 Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH.sub.2 PA1 m is 0-6; PA1 X is ##STR2## N--R.sup.a, or CH--NR.sup.b R.sup.c, where R.sup.a, R.sup.b, and R.sup.c are independently selected from the group consisting of hydrogen and C.sub.1 -C.sub.6 alkyl; PA1 Ar.sup.1 is phenyl substituted with one, two, or three moieties independently selected from the group consisting of hydrogen, halo, trifluoromethyl, trichloromethyl, C.sub.1 -C.sub.6 alkyl, and C.sub.1 -C.sub.6 alkoxy; or Ar.sup.1 is naphthyl; and PA1 R.sup.3, R.sup.4, and R.sup.5 are independently selected from the group consisting of hydrogen, halo, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, cyano, hydroxy, amino, --NHCONH.sub.2, nitro, --CONH.sub.2, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 -C.sub.8 cycloalkenyl, C.sub.3 -C.sub.8 cycloalkoxy, C.sub.1 -C.sub.10 alkylthio, C.sub.1 -C.sub.10 alkylamino, C.sub.2 -C.sub.6 alkanoyl, and C.sub.2 -C.sub.6 alkanoyloxy. PA1 1) ester or amide derivatives which may be cleaved by esterases or lipases; PA1 2) peptides which may be recognized by specific or nonspecific proteases; or PA1 3) derivatives that accumulate at a site of action through membrane selection of a prodrug form or a modified prodrug form; or any combination of 1 to 3, supra. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in H, Bundgaard, Design of Prodrugs, (1985). PA1 a) Ar.sup.1 is phenyl substituted with one or two moieties independently selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trichloromethyl, and trifluoromethyl; PA1 b) R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, trifluoromethyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, amino, --NHCONH.sub.2, --CONH.sub.2, vinyl, propenyl, methylthio, ethylthio, isopropylthio, methylamino, ethylamino, dimethylamino, acetyl, and acetoxy, with the proviso that at least one of R.sup.3, R.sup.4 and R.sup.5 is hydrogen unless all of R.sup.3, R.sup.4 and R.sup.5 are chloro, fluoro, bromo, trifluoromethyl, methyl, ethyl, methoxy, or ethoxy; PA1 c) n is 0, 1, or 2; PA1 d) m is 0, 1, or 2; and PA1 d) X, when combined to the heterocyclic group to which it is attached, forms 4-(cyclohexyl)piperazin-1-yl, 4-(piperidin-1-yl)piperidin-1-yl, 4-dimethylaminopiperidin-1-yl, 4-phenylpiperazin-1-yl, or 4-benzylpiperazin-1-yl.
hereinafter referred to as SEQ ID NO:1. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's. Substance P has the following amino acid sequence,
hereinafter referred to as SEQ ID NO:2.
Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin .alpha.), and neurokinin B (also known as neuromedin K and neurokinin .beta.). See, J. E. Maggio, Peptides, 6 (Supplement 3):237-243 (1985) for a review of these discoveries. Neurokinin A has the following amino acid sequence,
hereinafter referred to as SEQ ID NO:3. The structure of neurokinin B is the amino acid sequence,
hereinafter referred to as SEQ ID NO:4.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
In essence, this invention provides a class of potent non-peptide tachykinin receptor antagonists. By virtue of their non-peptide nature, the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.
Recent publications have described novel classes of non-peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such, newer non-peptidyl tachykinin receptor antagonists are found in European Patent Publication 591,040 A1, published Apr. 6, 1994; Patent Cooperation Treaty publication WO 94/01402, published Jan. 20, 1994; Patent Cooperation Treaty publication WO 94/04494, published Mar. 3, 1994; and Patent Cooperation Treaty publication WO 93/011609, published Jan. 21, 1993.